Co-regulation of primary mouse hepatocyte viability and function by oxygen and matrix

Although oxygen and extracellular matrix cues both influence differentiation state and metabolic function of primary rat and human hepatocytes, relatively little is known about how these factors together regulate behaviors of primary mouse hepatocytes in culture. To determine the effects of pericellular oxygen tension on hepatocellular function, we employed two methods of altering oxygen concentration in the local cellular microenvironment of cells cultured in the presence or absence of an extracellular matrix (Matrigel) supplement. By systematically altering medium depth and gas phase oxygen tension, we created multiple oxygen regimes (hypoxic, normoxic, and hyperoxic) and measured the local oxygen concentrations in the pericellular environment using custom-designed oxygen microprobes. From these measurements of oxygen concentrations, we derived values of oxygen consumption rates under a spectrum of environmental contexts, thus providing the first reported estimates of these values for primary mouse hepatocytes. Oxygen tension and matrix microenvironment were found to synergistically regulate hepatocellular survival and function as assessed using quantitative image analysis for cells stained with vital dyes, and assessment of secretion of albumin. Hepatocellular viability was affected only at strongly hypoxic conditions. Surprisingly, albumin secretion rates were greatest at a moderately supra-physiological oxygen concentration, and this effect was mitigated at still greater supra-physiological concentrations. Matrigel enhanced the effects of oxygen on retention of function. This study underscores the importance of carefully controlling cell density, medium depth, and gas phase oxygen, as the effects of these parameters on local pericellular oxygen tension and subsequent hepatocellular function are profound.National Institutes of Health (U.S.) (Grant P50-GM068762-08)National Institutes of Health (U.S.) (Grant R01-EB010246-04)National Institutes of Health (U.S.) (Grant R01-ES015241)National Institutes of Health (U.S.) (Grant P30-ES002109

The impact of early massive mergers on the chemical evolution of Milky Way-like galaxies: insights from NIHAO-UHD simulations

Recent observations of the Milky Way (MW) found an unexpected steepening of the star-forming gas metallicity gradient around the time of the Gaia-Sausage-Enceladus (GSE) merger event. Here we investigate the influence of early ($t_{\mathrm{merger}}\lesssim5$ Gyr) massive ($M_{\mathrm{gas}}^{\mathrm{merger}}/M_{\mathrm{gas}}^{\mathrm{main}}(t_{\mathrm{merger}})\gtrsim10\%$) merger events such as the Gaia-Sausage Enceladus merger in the MW on the evolution of the cold gas metallicity gradient. We use the NIHAO-UHD suite of cosmological hydrodynamical simulations of MW-mass galaxies to study the frequency of massive early mergers and their detailed impact on the morphology and chemistry of the gaseous disks. We find a strong steepening of the metallicity gradient at early times for all four galaxies in our sample which is caused by a sudden increase in the cold gas disk size (up to a factor of 2) in combination with the supply of un-enriched gas ($\sim0.75$ dex lower compared to the main galaxy) by the merging dwarf galaxies. The mergers mostly affect the galaxy outskirts and lead to an increase in cold gas surface density of up to 200% outside of $\sim8$ kpc. The addition of un-enriched gas breaks the self-similar enrichment of the inter-stellar-medium and causes a dilution of the cold gas in the outskirts of the galaxies. The accreted stars and the ones formed later out of the accreted gas inhabit distinct tracks offset to lower [$\alpha$/Fe] and [Fe/H] values compared to the main galaxy's stars. We find that such mergers can contribute significantly to the formation of a second, low-$\alpha$ sequence as is observed in the MW.Comment: 13 pages, 10 figures, accepted by MNRA

There is No Place Like Home -- Finding Birth Radii of Stars in the Milky Way

Stars move away from their birth places over time via a process known as radial migration, which blurs chemo-kinematic relations used for reconstructing the Milky Way formation history. One of the ultimate goals of Galactic Archaeology, therefore, is to find stars' birth aggregates in the disk via chemical tagging. Here we show that stellar birth radii can be derived directly from the data with minimum prior assumptions on the Galactic enrichment history. We recover the time evolution of the stellar birth metallicity gradient, $d$[Fe/H]($R$, $\tau$)/$dR$, through its inverse relation to the metallicity range as a function of age today, allowing us to place any star with age and metallicity measurements back to its birthplace, $R_b$. Applying our method to a high-precision large data set of Milky Way disk subgiant stars, we find a steepening of the birth metallicity gradient from 11 to 8 Gyr ago, which coincides with the time of the last major merger, Gaia-Sausage-Enceladus (GSE). This transition appears to play a major role in shaping both the age-metallicity relation and the bimodality in the [$\alpha$/Fe]-[Fe/H] plane. By dissecting the disk into mono-$R_b$ populations, clumps in the low-[$\alpha$/Fe] sequence appear, which are not seen in the total sample and coincide in time with known star-formation bursts. We estimated that the Sun was born at $4.5 \pm 0.4$ kpc from the Galactic center. Our $R_b$ estimates provide the missing piece needed to recover the Milky Way formation history, while the by-product,[Fe/H]$(R$, $\tau)$, can be used as the thus-far missing prior for chemical evolution modeling.Comment: Under review at Nature Letters, submitted Oct. 19, 202

Towards a developmental state? Provincial economic policy in South Africa

This paper explores the meaning of the developmental state for spatial economic policy in South Africa. Two main questions are addressed: do provincial governments have a role to play in promoting economic prosperity, and to what extent do current provincial policies possess the attributes of a developmental state? These attributes are defined as the ability to plan longer term, to focus key partners on a common agenda, and to mobilise state resources to build productive capabilities. The paper argues that the developmental state must harness the power of government at every level to ensure that each part of the country develops to its potential. However, current provincial capacity is uneven, and weakest where support is needed most. Many provinces seem to have partial strategies and lack the wherewithal for sustained implementation. Coordination across government appears to be poor. The paper concludes by suggesting ways provincial policies could be strengthened

Cats as a Risk for Transmission of Antimicrobial Drug-resistant Salmonella

Cats can shed antimicrobial drug−resistant Salmonella serotypes in the environment

Candidate gene prioritization based on spatially mapped gene expression: an application to XLMR

Motivation: The identification of genes involved in specific phenotypes, such as human hereditary diseases, often requires the time-consuming and expensive examination of a large number of positional candidates selected by genome-wide techniques such as linkage analysis and association studies. Even considering the positive impact of next-generation sequencing technologies, the prioritization of these positional candidates may be an important step for disease-gene identification

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights